Urea Linkages Research Articles

Polyurethane Recycling: Thermal Decomposition of 1,3-Diphenyl Urea to Isocyanates.

Substituted urea linkages are formed during the production of polyurethane foam. To chemically recycle polyurethane toward its key monomers via depolymerization (i.e., isocyanate), it is essential to break the urea linkages to form the corresponding monomers, namely, an isocyanate and an amine. This work reports the thermal cracking of a model urea compound (1,3-diphenyl urea, DPU) into phenyl isocyanate and aniline in a flow reactor at different temperatures. Experiments were performed at 350-450 °C, with a continuous feed of a solution of 1 wt.% DPU in GVL. In the temperature range studied, high conversion levels of DPU are achieved (70-90 mol%), with high selectivity towards the desired products (close to 100 mol%) and high average mole balance (∼95 mol%) in all cases.

Repurposing of Some VEGFR-2 Inhibitors: In Silico Molecular Dynamics Simulation (at 200 ns), Docking Based on the SARS-CoV-2-Main-Protease Inhibitor N3

The present study suggests the potential anti-SARS-CoV-2 activities of thirty five reported VEGFR-2 inhibitors containing the amide and urea linkers.

Amine-impregnated porous carbon–silica sheets derived from vermiculite with superior adsorption capability and cyclic stability for CO2 capture

Amine-functionalized adsorbents have become one of the most promising capture technologies for greenhouse gas mitigation. However, developing cost-effective adsorbents with high adsorption capacity and superior cyclic stability via temperature swing adsorption remains difficult. Herein, sandwich-like polyethyleneimine (PEI)-impregnated porous carbon–silica sheets derived from vermiculite (AEVCP) adsorbents were successfully synthesized via porous carbon network confined within acid activated expanded vermiculite derived silica (AEV) sheets and interlayer amine-functionalization with PEI impregnation. The effect of adsorption temperature on CO2 adsorption performances, adsorption/desorption kinetics and thermodynamics for AEVCP adsorbents were specifically discussed. The optimal AEVCP50 adsorbent possessed a large CO2 uptake of 1.84 mmol/g at 75 ℃ in 60 vol% CO2/40 vol% N2 and superior cyclic stability with 7.6 % decay after 10 cycles, due to the hierarchical porous structure and high thermal conductivity of porous carbon–silica sheets derived from vermiculite (AEVC) support. The unique sandwich-like features of AEVC support are favorable for the high amine loading, rapid CO2 diffusion and efficient capture. The interlayer carbon implantation and amine-functionalization with strong interlayer spatial confinement effect, can suppress the formation of urea linkages, avoid the persistent over-heating and excess amine agglomeration, and enhance the gas diffusion and thermal transfer during the adsorption isobar process, which ultimately lead to superior adsorption capability and cyclic stability for CO2 capture. This design approach of cost-effective adsorbents derived from natural minerals provides a new avenue for practical CO2 capture and separation processes.

New ICT-Based Ratiometric Two-Photon near Infrared Probe for Imaging Tyrosinase in Living Cells, Tissues, and Whole Organisms

Melanoma is a type of highly malignant and metastatic skin cancer. In situ molecular imaging of endogenous levels of the melanoma biomarker tyrosinase (TYR) may decrease the likelihood of mortality. In this study, we proposed the weakly fluorescent probe 1-(4-(2-(4-(dicyanomethylene)-4H-chromen-2-yl)vinyl)phenyl)-3-(4-hydroxybenzyl)urea (DCM-HBU), which releases a strong red-shifted fluorescent signal after a TYR-mediated oxidation followed by hydrolysis of the urea linkage. The large Stokes shift of the dye is owed to the recovery of the intramolecular charge transfer (ICT) effect. The resulting probe derivate shows a highly ratiometric fluorescence output. Furthermore, the simultaneous excitation by two near-infrared (NIR) photons of the released derivative of dicyanomethylene-4H-pyran (DCM-NH2) fluorophore could avoid the usual drawbacks, such as cellular absorption, autofluorescence, and light scattering, due to an usually short wavelength of the excitation light on biological systems, resulting in images with deeper tissue penetration. In addition, the probe is useful for the quantitative sensing of TYR activity in vivo, as demonstrated in zebrafish larvae. This new ratiometric two-photon NIR fluorescent probe is expected to be useful for the accurate detection of TYR in complex biosystems at greater depths than other one-photon excited fluorescent probes.

Insertion of an Amphipathic Linker in a Tetrapodal Tryptophan Derivative Leads to a Novel and Highly Potent Entry Inhibitor of Enterovirus A71 Clinical Isolates.

AL-471, the leading exponent of a class of potent HIV and enterovirus A71 (EV-A71) entry inhibitors discovered in our research group, contains four l-tryptophan (Trp) units bearing an aromatic isophthalic acid directly attached to the C2 position of each indole ring. Starting from AL-471, we (i) replaced l-Trp with d-Trp, (ii) inserted a flexible linker between C2 and the isophthalic acid, and (iii) substituted a nonaromatic carboxylic acid for the terminal isophthalic acid. Truncated analogues lacking the Trp motif were also synthesized. Our findings indicate that the antiviral activity seems to be largely independent of the stereochemistry (l- or d-) of the Trp fragment and also that both the Trp unit and the distal isophthalic moiety are essential for antiviral activity. The most potent derivative, 23 (AL-534), with the C2 shortest alkyl urea linkage (three methylenes), showed subnanomolar potency against different EV-71 clinical isolates. This finding was only observed before with the early dendrimer prototype AL-385 (12 l-Trp units) but remained unprecedented for the reduced-size prototype AL-471. Molecular modeling showed the feasibility of high-affinity binding of the novel l-Trp-decorated branches of 23 (AL-534) to an alternative site on the VP1 protein that harbors significant sequence variation among EV-71 strains.

Synthesis and Anti-Angiogenic Activity of Novel c(RGDyK) Peptide-Based JH-VII-139-1 Conjugates

Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the ανβ3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases.

Surface functionalization of ZnO nanoparticles by Schiff base oriented tetrapodal ligands at room temperature and their photocatalytic applications: A comparative account on effect of structure directing agent on photocatalysis

Surface modification of ZnO nanoparticles at room temperature and their photocatalytic activity • Synthesis of surface modified ZnO NPs i.e. P-ZnO, Q-ZnO, R-ZnO and S-ZnO by ligands P , Q , R and S respectively at room temperature of different shape and size. • Photocatalytic efficiency of P-ZnO, Q-ZnO, R-ZnO and S-ZnO towards photocatalytic degradation of Rh B dye in 90 min is ∼92%, 80%, 89% and 79% respectively. • ZnO nanoparticles modified by tetrapodal ligands having urea linker moieties (P-ZnO and R-ZnO) have shown very high photocatalytic degradation (∼89-92%). ZnO is very popular and extremely sought after semiconductor material and more so as in the nanocrystalline form. It is biocompatible having a tunable band gap (3-3.7 eV) at room temperature and popular for several optical properties of interest in many fields. Nanoparticles have a lot of surface defects which affect their stability, properties and applications. We use structure directing agents to control the morphology of ZnO nanoparticles and also to control surface defects. We utilised four Schiff base oriented tetrapodal ligands (P, Q, R and S) as the structure directing agents for synthesis of surface modified ZnO nanoparticles i.e. P-ZnO [nanospheres (50-55 nm)], Q-ZnO [nanorods of length (∼1-2 µm) and breadth (∼130-170 nm)], R-ZnO [fibrous/entangled mesh] and S-ZnO [nanorods of length (30-40 nm) and breadth (5-20 nm)] at room temperature i.e. 30-40°C. The application of P-ZnO, Q-ZnO, R-ZnO and S-ZnO are further explored for photocatalytic degradation of Rhodamine B dye under UV lamp (90 min). The efficiency of P-ZnO, Q-ZnO, R-ZnO and S-ZnO towards photocatalytic degradation of Rhodamine B dye was ∼92%, ∼80%, ∼89% and ∼79% respectively.

In silico molecular docking, dynamics simulation and repurposing of some VEGFR-2 inhibitors based on the SARS-CoV-2-main-protease inhibitor N3

The global and rapid spread of the novel human coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has brought immediate urgency to the discovery of favorable targets for COVID-19 treatment. Here, we consider drug reuse as an attractive methodology for drug discovery by reusing existing drugs to treat diseases other than their initial indications. Here, we review current information concerning the global health issue of COVID-19 including VEGFR-2 inhibitors. Besides, we describe computational approaches to be used in drug repurposing and highlight examples of in silico studies of drug development efforts against SARS-CoV-2. The present study suggests the potential anti-SARS-CoV-2 activities of 35 reported VEGFR-2 inhibitors containing the amide and urea linkers. Nineteen members revealed the best in silico results and hence, were subjected to further molecular dynamics (MD) simulation for their inhibitory activities against SARS-CoV-2 Mpro across 100 ns. Furthermore, MD simulations followed by calculations of the free energy of binding were also carried out for the most promising ligand-pocket complexes from docking studies to clarify some information on their dynamic and thermodynamic properties and approve the docking results. These results we obtained probably provided an excellent lead candidate for the development of therapeutic drugs against COVID-19. Communicated by Ramaswamy H. Sarma

A TiO2/polyurethane Composite for Photodegradation of Formaldehyde via Covalently Incorporation of Amino-functionalized TiO2

In this study, a TiO2/polyurethane composite (PU-TiO2) for photodegradation of formaldehyde was prepared based on TiO2 amino-functionalized with 3-aminopropyltriethoxysilane (APTS). FTIR, XPS, TG and TEM measurements demonstrated the successful amino-functionalization of TiO2 by APTS. Then the NH2-TiO2 were incorporated into polyurethane (PU) through urea linkages, and the thermal stability, mechanical properties as well as degradation efficiency of PU-TiO2 were investigated. PU-TiO2 possessed good thermal stability both in the storage and application. Compared with PU physically blended with TiO2, PU-TiO2 showed improved compatibility between PU and NH2-TiO2, evidenced by the enhanced mechanical properties. Most importantly, PU- TiO2 presented a good photoactivity for the degradation of formaldehyde.

Design, Synthesis, and Biological Study of Novel Farnesoid X Receptor Agonist for the Treatment of Cholestatic Liver Disease

AbstractFarnesoid X receptor (FXR) plays an important role in regulating bile acid homeostasis, which is considered as an innovative target for cholestasis. In this study, we have hybrid FXR agonists LY2562175 with GW4064, and we introduced the urea linker to avoid the potentially toxic scaffold stilbene in GW4064. These efforts provided FXR partial agonist 1 (EC50=282 nM, efficacy=70 %), which binds very tightly to the pocket of FXR by forming an ionic bond with Arg331, the residue is vital to the activity of FXR. Indeed, compound 1 exhibited little cytotoxicity in the MTT assay. Moreover, compound 1 revealed a comparative protective effect against ANIT‐induced cholestasis to that of obeticholic acid, the most advanced FXR agonist in this field. Further studies exhibited that partial agonist 1 exerts multiple synergetic mechanisms on bile acid homeostasis in vivo: 1) Decreasing hepatic uptake and increasing efflux of bile acids by regulating the gene expression of Ntcp, Bsep, and Mrp2. 2) Reducing hepatic bile acid synthesis by inhibiting the expressions of Cyp7a1 and Cyp8b1. 3) Increasing hepatic bile acid metabolism by promoting gene expression of Sult2a1. In conclusion, these results suggested that compound 1 is a promising FXR partial agonist suitable for further study.

Synthesis of dual‐stimuli‐responsive polyurethane shape memory nanocomposites incorporating isocyanate‐functionalized Fe3O4 nanoparticles

AbstractThermally and magnetically stimulated shape memory polyurethane (PU) nanocomposites were synthesized for intravascular stent applications. For this end, Fe3O4 magnetic nanoparticles (MNPs) were modified with octadecyl isocyanate (OD) to increase their affinity with the PU matrix by formation of the covalent urea linkages. The results showed that the OD‐grafted MNPs were replaced instead of carbonyl groups of polycaprolactone (PCL) soft segments in hydrogen bond formation with the urethane linkages. This led to higher phase separation degrees among the soft and hard phases, thereby PCL chains could reveal higher crystallization potential. Mechanical studies showed that the nanocomposites had high mechanical strength, Young's modulus, and elongation at break, which improve their practical applications. The nanocomposites showed thermo‐responsive shape memory behavior with a high shape recovery and shape fixity ratios due to the presence of the crystallizable PCL segments. The nanocomposite containing 10 wt% of the OD‐grafted MNPs could recover its original shape (during 90s) in a relatively weak alternating magnetic field (350 kHz and 12.9 kA/m). These results indicated that the prepared nanocomposites could be used to normalize the narrowed blood vessels through the remotely and magnetically‐controllable restricted shape recovery process.

Hypochlorous Acid-Activated Multifunctional Fluorescence Platform for Depression Therapy and Antidepressant Efficacy Evaluation.

Current diagnosis of depression rests on the symptoms, so it still lacks objective criteria. Meanwhile, existing treatment of depression is dominated by antidepressants, which produce troublesome side effects and usually require months to achieve effect. Therefore, more reliable diagnostic criteria and effective therapy are urgently needed. Some core hallmarks in the etiology of depression have been established, including declined neurotransmitters and inflammatory responses, manifesting in oxidative stress. Thus, we fabricated a HClO-triggered multifunctional fluorescence platform (MB-Rs) for simultaneous neurotransmitter/antidepressant delivery and efficacy evaluation. In MB-Rs, although a urea linkage could be specifically cut off by HClO, methylene blue (MB) endowed with excellent anti-inflammatory and optical properties was covalently linked with neurotransmitters (dopamine or 5-hydroxytryptamine) or antidepressants (fluoxetine). Encountering excess HClO in the brain of mice with depression, MB-Rs released corresponding antidepressants and MB with anti-inflammatory and bright fluorescence. By relieving oxidative stress, inflammation, and coinstantaneous increasing neurotransmitters, MB-Rs elicited better antidepressant response and fewer side effects compared with clinical antidepressants. Furthermore, MB-Rs successfully evaluated the efficacy of antidepressants in mice based on HClO-induced fluorescence. Therefore, this work provides a promising platform for depression diagnosis and treatment.

Synthesis of a new chitosan-p-tert-butylcalix[4]arene polymer as adsorbent for toxic mercury ion.

In this paper, we have synthesized a novel chitosan-p-tert-butylcalix[4]arene polymer (CCP) as a highly efficient adsorbent for mercury ion (Hg2+) removal from water. In fact, a lower rim diamine derivative of p-tert-butylcalix[4]arene has been cross-linked with chitosan chain by carbonyl diimidazole (CDI) as the linker. CDI forms a urea linkage between calix[4]arene diamine derivative and amine groups of the chitosan polymeric chain. The structure and properties of the new polymer were characterized by Fourier transform infrared spectroscopy, X-ray diffraction and scanning electron microscope. Also, the adsorption capacity of CCP was studied towards Hg2+ in aqueous medium by inductively coupled plasma-optical emission spectrometry. Interestingly, the results showed a considerable adsorption capacity for CCP in comparison with chitosan. Therefore, CCP can be introduced as a promising adsorbent for the elimination of Hg2+ from wastewaters. Moreover, because of the conformity of adsorption kinetic with pseudo-second-order kinetic models, it can be concluded that chemical adsorption has an important role between functional groups on CCP polymer and Hg2+ ions. In addition, according to Freundlich isotherm, the CCP surface was heterogeneous with different functional groups.

Dynamic and Reprocessable Fluorinated Poly(hindered urea) Network Materials Containing Ionic Liquids to Enhance Triboelectric Performance

Triboelectric nanogenerators (TENGs), a newly developed energy harvesting device that converts surrounding environmental mechanical stimuli into electricity, have been significantly explored as an ideal long-term power source for electrical devices. Despite recent advances, the development of advanced TENG devices with sufficient outputs to sustainably power electronic devices and rapid self-healability under mild conditions to improve their lifetime and function is highly demanded. Here, we report a robust self-healable and reprocessable TENG fabricated with a covalent adaptive network based on mechanically strong fluorinated poly(hindered urea) (F-PHU) integrated with ionic liquid as an efficient dielectric material to improve its triboelectric efficiency and self-healing capability simultaneously. The synthesis and integration of a well-defined reactive copolymer having both pendant fluorinated and t-butylamino bulky groups are the key to fabricate robust F-PHU networks containing fluorinated dangling chains that can interact with ionic liquids to induce ionic polarization, which raises the dielectric constant and thus increases triboelectric performance. They also are cross-linked with dynamic bulky urea linkages for rapid self-healability and high reprocessability through their reversible exchange reactions at moderate temperatures. The developed ionic F-PHU materials exhibit a high TENG output performance (power density of 173.0 mW/m2) as well as high TENG output recovery upon repairing their surface damages. This work demonstrates that such a synergistic design of triboelectric ionic F-PHU materials could have great potential for applications requiring high-performance and long-lasting energy harvesting.

Chemical and physical effects of polyurethane-precursor-based reactive modifier on the low-temperature performance of bitumen

The use of novel polyurethane-precursor-based reactive modifier (PRM) to produce high-performance modified bitumen provides great benefits in terms of both performance improvement and environmental protection. Given the complexity of the chemical composition of bitumen, its chemical interaction with PRM and the modification effect on bitumen performance are of great interest. To fundamentally understand the chemical reactions and low-temperature behaviours of PRM-modified bitumen, physicochemical characterisations and quantum-chemical calculations were performed from chemical, thermal, morphological, and mechanical aspects. The results were interpreted based on the reactions between PRM and bitumen model compounds. It shows that the carbamate, urea, and amide linkages are formed by the reactions of PRM with active sites in asphaltenes and resins, which eventually cause crosslinking polymerisation owing to the asphaltene fraction. The modification process promotes the conversion of the resin to asphaltene and reconfiguration of asphaltene, which accordingly increases the facilitation of the natural segregation of maltene and asphaltene. With the strengthening of the reconfiguration and crosslinking of asphaltene molecules, considerably improved stiffness and fracture resistance are observed. However, the concurrent changes in bitumen composition and chemical structures result in a slight increase followed by a decrease in the low-temperature properties with an increase in the PRM concentration. In the presence of excessive PRM, the modified bitumen becomes more susceptible to large deformations. This study not only provides a reference for understanding the PRM modification mechanism but could also serve as a guidance for the further application of PRM-modified bitumen.

Reversible Capture and Release of a Ligand Mediated by a Long-Range Relayed Polarity Switch in a Urea Oligomer.

Ethylene-bridged oligoureas characterized by a continuous, switchable chain of hydrogen bonds and carrying a binding site (an N,N′-disubstituted urea) for a hydrogen-bond-accepting ligand (a phosphine oxide) were synthesized. These oligomers show stronger ligand binding when the binding site is located at the hydrogen-bond-donating terminus than when the same binding site is at the hydrogen-bond-accepting terminus. An acidic group at the terminus remote from the binding site allows hydrogen bond polarity, and hence ligand binding ability, to be controlled remotely by a deprotonation/reprotonation cycle. Addition of base induces a remote conformational change that is relayed through up to five urea linkages, reducing the ability of the binding site to retain an intermolecular association to its ligand, which is consequently released into solution. Reprotonation returns the polarity of the oligomer to its original directionality, restoring the function of the remote binding site, which consequently recaptures the ligand. This is the first example of a synthetic molecular structure that relays intermolecular binding information, and these “dynamic foldamer” structures are prototypes of components for chemical systems capable of controlling chemical function from a distance.

Amyloidogenic immunoglobulin light chain kinetic stabilizers comprising a simple urea linker module reveal a novel binding sub-site

In immunoglobulin light chain (LC) amyloidosis, the misfolding, or misfolding and misassembly of LC a protein or fragments thereof resulting from aberrant endoproteolysis, causes organ damage to patients. A small molecule “kinetic stabilizer” drug could slow or stop these processes and improve prognosis. We previously identified coumarin-based kinetic stabilizers of LCs that can be divided into four components, including a “linker module” and “distal substructure”. Our prior studies focused on characterizing carbamate, hydantoin, and spirocyclic urea linker modules, which bind in a solvent-exposed site at the VL-VL domain interface of the LC dimer. Here, we report structure–activity relationship data on 7-diethylamino coumarin-based kinetic stabilizers. This substructure occupies the previously characterized “anchor cavity” and the “aromatic slit”. The potencies of amide and urea linker modules terminating in a variety of distal substructures attached at the 3-position of this coumarin ring were assessed. Surprisingly, crystallographic data on a 7-diethylamino coumarin-based kinetic stabilizer reveals that the urea linker module and distal substructure attached at the 3-position bind a solvent-exposed region of the full-length LC dimer distinct from previously characterized sites. Our results further elaborate the small-molecule binding surface of LCs that could be occupied by potent and selective LC kinetic stabilizers.

Development and characterization of flame retardant property in flexible polyurethane foam

Polyurethane foam (PF) is an essential polymer which is widely used in everyday applications either directly or indirectly by the fast moving world. By changing the composition of polyol and isocyanate, these foams can be classified into rigid polyurethane foams (PUFRs) and flexible polyurethane foams (PUFFs). Due to the open cell structure, low decomposition temperature of the monomers, polyurethane foams (PFs) are easily prone to flammability which can prove to be hazardous to its end users. In this present study, a list of potential flame retardants (FRs) such as expandable graphite (EG), magnesium hydroxide (MGH), nano-titanium dioxide (NTD), organo-montmorillonite (OMMT), and MGH with OMMT, EG as a synergetic combinations were used. EG was prepared at the laboratory scale and its morphology was analyzed by scanning electron microscope (SEM). The SEM substantiates the formation of worm like structure in EG which helps in suppressing the growth of flame. Various testing methods were used to characterise the generated PUFFs, including morphology using optical microscope (OM), functional groups using Fourier infrared spectroscopy (FTIR), and flame retardant (FR) property using an Underwriters laboratories (UL) 94 horizontal burning (HB). An OM image confirms the formation of open cell structure which shows PUFF. The peak in the range 2270 cm−1 and 2240 cm−1 was not observed in the FTIR spectra for any of the PUFF samples prepared. This demonstrates and proves that the isocyanate utilised is totally transformed to PUFF, implying that urea and urethane linkages are formed with the addition of polyol and fillers. Among all PUFFs, the UL 94 HB test affirms that the combination of EG + MGH has the best FR property with 0.27 mm/s rating because of the synergistic effect. This confirms the suitability of PUFF in applications when compared to the other chosen in the present investigation.

Synthesis and screening of kojic acid derivatives for their bio-efficacy against diamondback moth (Plutella xylostella L.)

Kojic acid derivatives containing urea and thiourea linkage has been synthesized and tested against second instar larvae of diamondback moth (Plutella xylostella) under laboratory conditions. Most of the compounds showed ≥ 50% mortality against second instar larvae of P. xylostella. Compound 3b was found more effective against P. xylostella (83.3% mortality at 10,000 ppm) after 96 h of treatment. Other compounds with significant mortality were 4h, 4j (80% mortality at 10,000 ppm), and 3c, 4c, 4m (76.6% mortality at 10,000 ppm). The most promising compounds among the synthesized library could be candidates for further development to obtain lead molecules.

Discovery of memantyl urea derivatives as potent soluble epoxide hydrolase inhibitors against lipopolysaccharide-induced sepsis.

Sepsis, a systemic inflammatory response, caused by pathogenic factors including microorganisms, has high mortality and limited therapeutic approaches. Herein, a new soluble epoxide hydrolase (sEH) inhibitor series comprising a phenyl ring connected to a memantyl moiety via a urea or amide linkage has been designed. A preferential urea pharmacophore that improved the binding properties of the compounds was identified for those series via biochemical assay invitro and invivo studies. Molecular docking displayed that 3,5-dimethyl on the adamantyl group in B401 could make van der Waals interactions with residues at a hydrophobic pocket of sEH active site, which might indirectly explain the subnanomolar level activities of memantyl urea derivatives invitro better than AR-9281. Among them, compound B401 significantly improved the inhibition potency with human and murine sEH IC50 values as 0.4nM and 0.5nM, respectively. Although the median survival time of C57BL/6 mice in LPS-induced sepsis model was slightly increased, the survival rate did not reach significant efficacy. Based on safety profile, metabolic stability, pharmacokinetic and invivo efficacy, B401 demonstrated the proof of potential for this class of memantyl urea-based sEH inhibitors as therapeutic agents in sepsis.